The goal of this research is to achieve tumor specific delivery of radiosensitizing drugs by use of ligands that bind to radiation-inducible receptors within cancer. The tumor vascular endothelium responds to ionizing radiation in a similar manner in all tumor models. We, therefore, utilized phage displayed libraries to select peptide ligands that bind within the microvasculature of several classes of tumor models. We have completed side-by-side comparisons of tumor-specific phage and found that the phage-displayed HGDPNHVGGSSV peptide has sustained binding (9 days) within the tumor microvasculature following treatment with low dose irradiation. Tumor sections show that the peptide binds to the tumor vascular endothelium. In the proposed Aims, we will characterize the mechanism of HGDPNHVGGSSV binding within irradiated microvasculature. We will also study the effectiveness of this peptide at achieving tumor specific drug delivery within the microvasculature of irradiated tumors by means of a nanoparticulate delivery vehicle. We will deliver a gene expression system to the tumor and study targeting and biological effects of the gene product. The proposed Aims will test the hypothesis that HGDPNHVGGSSV peptide-conjugated nanoparticles provide tumor specific targeting of drug delivery to irradiated tumors. In Aim 1, we will determine the mechanisms by which HGDPNHVGGSSV binds to irradiated tumor microvasculature. Affinity purification will be used to identify proteins that bind to this peptide. We have found that the HGDPNHVGGSSV peptide precipitates an endothelial protein. We will verify the role of this protein receptor during peptide binding within irradiated tumors. In Aim 2, we will determine the bioavailability of radiation sensitizing drugs by use of peptide-nanoparticle conjugated drug delivery systems targeted to radiation- inducible receptors within tumor vessels. We will conjugate peptides to nanoparticles and determine whether tumor-specific binding is achieved. In Aim3, we will determine whether tumor specific drug delivery and efficacy is facilitated by nanoparticle conjugation to HGDPNHVGGSSV irradiated prostate tumors. We will determine whether HGDPNHVGGSSV peptide-nanoparticle conjugates achieve tumor specific binding and maintains its biological activity. We envision that radiation sensitizing drugs can be targeted specifically to tumor micro-vasculature by use of peptide conjugated drug delivery systems during radiotherapy.